title: A role for BLM in double-strand break repair pathway choice: prevention of CtIP/Mre11-mediated alternative nonhomologous end-joining.
abstract: The choice of the appropriate double-strand break (DSB) repair pathway is essential for the maintenance of genomic stability. Here, we show that the Bloom syndrome gene product, BLM, counteracts CtIP/MRE11-dependent long-range deletions (>200 bp) generated by alternative end-joining (A-EJ). BLM represses A-EJ in an epistatic manner with 53BP1 and RIF1 and is required for ionizing-radiation-induced 53BP1 focus assembly. Conversely, in the absence of 53BP1 or RIF1, BLM promotes formation of A-EJ long deletions, consistent with a role for BLM in DSB end resection. These data highlight a dual role for BLM that influences the DSB repair pathway choice: (1) protection against CtIP/MRE11 long-range deletions associated with A-EJ and (2) promotion of DNA resection. These antagonist roles can be regulated, according to cell-cycle stage, by interacting partners such as 53BP1 and TopIII, to avoid unscheduled resection that might jeopardize genome integrity.
authors.affiliation: CNRS UMR217, CEA, DSV, Institut de Radiobiologie Cellulaire et Moléculaire, 18 Route du Panorama, Fontenay aux Roses F-92265, France.
authors.forename: Anastazja
authors.initials: A
authors.lastname: Grabarz
authors.forename: Josée
authors.initials: J
authors.lastname: Guirouilh-Barbat
authors.forename: Aurélia
authors.initials: A
authors.lastname: Barascu
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pennarun
authors.forename: Diane
authors.initials: D
authors.lastname: Genet
authors.forename: Emilie
authors.initials: E
authors.lastname: Rass
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Germann
authors.forename: Pascale
authors.initials: P
authors.lastname: Bertrand
authors.forename: Ian D
authors.initials: ID
authors.lastname: Hickson
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Lopez
mesh_terms: D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004706:Endodeoxyribonucleases; D006801:Humans; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D009687:Nuclear Proteins; D004706:Endodeoxyribonucleases; D000076228:MRE11 Homologue Protein; C410741:RBBP8 protein, human; C097151:Bloom syndrome protein; D053484:RecQ Helicases